The purpose of this revised grant application is to solicit funding to add a molecular genetic component to the extensive epidemiologic data on Substance Use Disorders (SUD) available in the Iowa Adoption Studies. These epidemiologic studies include over 900 adult adoptees, separated at birth from biologic parents, interviewed over a 20 year period, who are now being re-interviewed with a focus upon lifetime substance use/abuse/dependency. Over the past two decades in studies of these adoptees, our research group has shown significant genetic and environmental effects and gene-environment interactions that affect both early life risk factors for substance abuse and the course of adult substance use/abuse/dependency. The adoption paradigm has furthered the study of the development of risk behaviors for SUD by allowing the examination of how genetic factors may interact with environmental factors such as parenting behaviors in the adoptive home and is the study design of choice for the detection of these important gene environment interactions. In this application, we hypothesize that genetic variability and certain gene environment interactions are responsible for increased vulnerability to SUD, and in particular, Nicotine, Alcohol and Marijuana abuse/dependence. To test this hypothesis we will: 1) Conduct follow-up behavioral and cognitive assessments (including quantitative measures of SUD risk), then collect DNA samples from the our well characterized cohort of adoptees 2) conduct candidate and single nucleotide polymorphism analysis with respect to the best validated candidate genes or loci, and 3) analyze the resulting data using association and multifactorial regression to create a testable model of single gene, gene* gene, environmental and gene*environment contributions to the susceptibility to SUD. As direct result of these experiments, we will determine specific gene and gene-environment interactions that contribute to increased vulnerability to SUD. The identification of these interactions, and in particular gene x environment interactions, is important as it will allow the development of more effective biological and environmental (e.g. changing parenting behaviors or the formulation of new behavioral treatment strategies) interventions for the treatment of SUD. As an indirect result of these experiments, the scientific community will gain a unique and valuable genetic resource that can be utilized by other investigators of genetic and epidemiologic vulnerability to SUD in showing that these Iowa Adoption Studies through the NIDA Genetics Consortium. [unreadable] [unreadable]